Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function
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TRPV2 is a ligand-operated temperature sensor with poorly defined pharmacology. Here, we combine calcium imaging and patch-clamp electrophysiology with cryo-electron microscopy (cryo-EM) to explore how TRPV2 activity is modulated by the phytocannabinoid Δ9-tetrahydrocannabiorcol (C16) and by probenecid. C16 and probenecid act in concert to stimulate TRPV2 responses including histamine release from rat and human mast cells. Each ligand causes distinct conformational changes in TRPV2 as revealed by cryo-EM. Although the binding for probenecid remains elusive, C16 associates within the vanilloid pocket. As such, the C16 binding location is distinct from that of cannabidiol, partially overlapping with the binding site of the TRPV2 inhibitor piperlongumine. Taken together, we discover a new cannabinoid binding site in TRPV2 that is under the influence of allosteric control by probenecid. This molecular insight into ligand modulation enhances our understanding of TRPV2 in normal and pathophysiology.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 7483 |
| Tidsskrift | Nature Communications |
| Vol/bind | 13 |
| Udgave nummer | 1 |
| Antal sider | 18 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
This study was supported by the Swedish Research Council (2014–3801; P.M.Z. and 2020-01693; G.N. as well as 2012–2243 and 2016-04474; P.G.) and the Medical Faculty of Lund University – ALF (Dnr. ALFSKANE-451751; P.M.Z), Hjärnfonden/the Swedish Brain Foundation (FO2020-0188 and FO2022-0292; P.M.Z.), Stiftelsen Olle Engkvist Byggmästare (189–290; P.M.Z.), Albert Påhlssons stiftelse (P.M.Z.), Alfred Österlunds stiftelse (P.M.Z.); Knut och Alice Wallenbergs Stiftelse (2015.0131 and 2020.0194; P.G.), The Lundbeck Foundation (R133-A12689, R313-2019-774 and R346-2020-2019; P.G.), the Danish Council for Independent Research (9039-00273; P.G.) and the Crafoord Foundation (20170818; P.G.); the Czech Science Foundation (grant number 22-13750S; V.V.). Support from the DFG Cluster of Excellence EXC2051 Balance of the Microverse—Project-ID 390713860, the DFG Collaborative Research Center 1507 “Membrane-associated protein assemblies, machineries and supercomplexes” (Project-ID 450648163, P11 to U.A.H.) and the National Institutes of Health R01GM081340 (R.G.) is kindly acknowledged. We would like to acknowledge Benedikt Goretzki, Sabine Häfner and Michal Mitro for technical support. We would also like to thank Julian Conrad, Dustin Morado and Marta Carroni at SciLifeLab Stockholm as well as Tillmann Hanns Pape at the Core Facility for Integrated Microscopy (CFIM) at University of Copenhagen for assistance with the grid screening and Cryo-EM data collection. The Cryo-EM Swedish National Facility at SciLifeLab is funded by the Knut and Alice Wallenberg, Family Erling Persson and Kempe Foundations, SciLifeLab, Stockholm University and Umeå University. The Danish Cryo-EM Facility at CFIM, University of Copenhagen is supported by Novo-Nordisk Foundation grant id NNF14CC0001.
Funding Information:
This study was supported by the Swedish Research Council (2014–3801; P.M.Z. and 2020-01693; G.N. as well as 2012–2243 and 2016-04474; P.G.) and the Medical Faculty of Lund University – ALF (Dnr. ALFSKANE-451751; P.M.Z), Hjärnfonden/the Swedish Brain Foundation (FO2020-0188 and FO2022-0292; P.M.Z.), Stiftelsen Olle Engkvist Byggmästare (189–290; P.M.Z.), Albert Påhlssons stiftelse (P.M.Z.), Alfred Österlunds stiftelse (P.M.Z.); Knut och Alice Wallenbergs Stiftelse (2015.0131 and 2020.0194; P.G.), The Lundbeck Foundation (R133-A12689, R313-2019-774 and R346-2020-2019; P.G.), the Danish Council for Independent Research (9039-00273; P.G.) and the Crafoord Foundation (20170818; P.G.); the Czech Science Foundation (grant number 22-13750S; V.V.). Support from the DFG Cluster of Excellence EXC2051 Balance of the Microverse—Project-ID 390713860, the DFG Collaborative Research Center 1507 “Membrane-associated protein assemblies, machineries and supercomplexes” (Project-ID 450648163, P11 to U.A.H.) and the National Institutes of Health R01GM081340 (R.G.) is kindly acknowledged. We would like to acknowledge Benedikt Goretzki, Sabine Häfner and Michal Mitro for technical support. We would also like to thank Julian Conrad, Dustin Morado and Marta Carroni at SciLifeLab Stockholm as well as Tillmann Hanns Pape at the Core Facility for Integrated Microscopy (CFIM) at University of Copenhagen for assistance with the grid screening and Cryo-EM data collection. The Cryo-EM Swedish National Facility at SciLifeLab is funded by the Knut and Alice Wallenberg, Family Erling Persson and Kempe Foundations, SciLifeLab, Stockholm University and Umeå University. The Danish Cryo-EM Facility at CFIM, University of Copenhagen is supported by Novo-Nordisk Foundation grant id NNF14CC0001.
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© 2022, The Author(s).
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